Lyme disease is a multisystem, multistage, inflammatory illness caused by the tick-borne spirochete, Borrelia burgdorferi. In North America, Lyme arthritis is the major manifestation of the disease. Although inflammation directed at persistence of B. burgdorferi antigens plays an important role in persistent arthritis, little is known about the Borrelia proteins involved in infection and pathogenesis. Our long-term goal is to elucidate virulence determinants and mechanisms of virulence as a prerequisite to developing therapeutic protocols for treatment of Lyme arthritis and prevention of the disease. The objective of this application is to identify new Borrelia virulence factors and immunogens that are important for Lyme borreliosis. The proposed research is based on our recent finding that the Hk2-Rrp2 two-component signaling pathway, which is essential for Borrelia virulence in the mammalian host, governs expression of a group of mammalianinfection associated immunogens of B. burgdorferi. We hypothesize that these immunogens play important roles in Borrelia infection and pathogenesis. To test this hypothesis, we propose 1), to identify the mammalian infection-associated immunogens controlled by the Hk2-Rrp2 two-component signaling pathway; 2), to construct isogenic mutants defective in producing these immunogens in a virulent strain of B. burgdorferi, and 3) to examine the mutants' ability to infect mice and cause disease in the murine Lyme arthritis model. [unreadable] [unreadable] RELEVANCE: Accomplishing the specific aims outlined in this proposal will likely yield the discovery of new virulence factors that are essential for Borrelia infection and pathogenesis in mammalian hosts, which will not only advance our understanding the molecular mechanism of the pathogenesis of Lyme disease, but also will identify new potential vaccine target(s) for prevention and treatment of Lyme arthritis, and/or an agents of serological tests for Lyme disease. [unreadable] [unreadable] [unreadable]